PROJECT SUMMARY/ABSTRACT T cells expressing the gamma delta T cell receptor (?? T cells) are strategically located at mucosal barriers such as the gastrointestinal tract. As such, ?? T cells are thought to be ideally placed for rapid immunity to pathogens and are also thought to be a critical component of innate immunity and epithelial barrier integrity, both of which become compromised in the elderly. Even though many clinically relevant human pathogens, such as Listeria monocytogenes (LM), invade through the intestinal mucosa of the elderly, our understanding of intestinal T cell responses to relevant pathogens or vaccinations in these populations remains incomplete. We have recently identified a subset of protective long-lived memory ?? T cells after oral but not intravenous immunization that resemble memory ?? T cells described in humans. Surprisingly, this pathogen-elicited memory ?? T cell response is enhanced in aged mice and is associated with an enhanced antigen-specific CD8 T cell response. Thus, the central aim of this proposal is to determine the role and protective potential of pathogen-elicited memory ?? T cells in aged mice. This proposal will test the central hypothesis that pathogen-elicited memory ?? T cells provide help to the adaptive immune response in aged mice. In the aims outlined below, the aged response after oral immunization will be explored. Additionally, whether memory ?? T cells provide help to CD8 T cells in aged mice will be determined. Specific Aim 1: Evaluate the LM-elicited adaptive T cell response in aged mice after oral LM immunization. Specific Aim 2: Evaluate LM-elicited adaptive ?? T cells contribution to protective immunity in aged mice. Although in the past few years' substantial progress has been made in our understanding of the mucosal immune response in the intestine, serious gaps in our knowledge remain. Many studies utilize non-physiologic infection routes to study immune responses to mucosal pathogens but models that more closely reproduce the human condition are needed. The goal of this proposed study is to understand mechanisms regulating enhanced pathogen-elicited T cell responses in aged mice after oral immunization. This is highly significant for inducing protective immunity and developing successful vaccination strategies in the elderly population and could lead to significant advances concerning the manipulation of immunity in aged individuals.